Hepatocellular carcinoma (HCC) is the most common liver cancer and is featured with prominent disparity in incidence and mortality rate between males and females. Phospholipases are enzymes that hydrolyze phospholipids (PLs) either with acylhydrolase or phosphodiesterase activity. Phospholipases are involved in lipid metabolism, membrane dynamics, cellular signaling, migration, growth, and cell death. Alterations of phospholipases in hepatic tissues play important roles in pathogenesis, progression, and gender disparity of HCC. Thus, inhibition of phospholipases may be novel targets for HCC chemotherapeutics. This book chapter summarizes the different types of phospholipases and their expressions in cancers, focuses on the potential mechanisms by which these esterases mediate carcinogenesis, and explains how the inhibition of phospholipases may be targets for HCC treatment.